The identification of human tumor antigens recognized by the autologous host is yielding new and promising target molecules for immunotherapy, diagnosis and monitoring of human cancer (van der Bruggen P, et al. 1991. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254:1643-47; Gaugler, B., et al. Human gene MAGE-3 codes for an antigen recognized on a melanoma by autologous cytolytic T lymphocytes. J. Exp. Med. 1994; 179: 921-30; Kawakami, Y., et al. Cloning of the gene for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc. Natl. Acad. Sci. USA. 1994; 91: 3515-19 and Chen, Y.-T., et al. A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening. Proc. Natl. Acad. Sci. USA. 1997; 94: 1914-18). Studies of the cellular and humoral immune response to cancer have revealed an extensive repertoire of tumor antigens recognized by the immune system, collectively termed the cancer immunome (Jager D, et al. Identification of a tissue-specific putative transcription factor in breast tissue by serological screening of a breast cancer library. Cancer Res 2001 Mar. 1; 61(5):2055-61).
The immunome is composed largely of antigens defined by T-cell epitope cloning (van der Bruggen P, et al. 1991. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254:1643-47; Gaugler, B., et al. Human gene MAGE-3 codes for an antigen recognized on a melanoma by autologous cytolytic T lymphocytes. J. Exp. Med. 1994; 179: 921-30; Kawakami, et al. Cloning of the gene for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc. Natl. Acad. Sci. USA. 1994; 91: 3515-19; Boel, P., et al. BAGE: a new gene encoding an antigen recognized on human melanomas by cytolytic T lymphocytes. Immunity 1995; 2: 167-75. (PMID: 7895173); Van den Eynde, B., et al. A new family of genes coding for an antigen recognized by autologous cytolytic T lymphocytes on a human melanoma. J. Exp. Med. 1995; 182: 689-98. (PMID: 7544395)), MHC peptide elution (Skipper J C, et al. An HLA-A2-restricted tyrosinase antigen on melanoma cells results from posttranslational modification and suggests a novel pathway for processing of membrane proteins. J Exp Med 1996 Feb. 1; 183(2):527-34; Cox A L, et al. Identification of a peptide recognized by five melanoma-specific human cytotoxic T cell lines. Science 1994 Apr. 29; 264(5159):716-9; Pascolo S, et al. A MAGE-A1 HLA-A A*0201 epitope identified by mass spectrometry. Cancer Res 2001 May 15; 61(10):4072-7), and serological expression cloning (SEREX, Chen, Y.-T., et al. A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening. Proc. Natl. Acad. Sci. USA. 1997; 94: 1914-18; Jager D, et al. Identification of a tissue-specific putative transcription factor in breast tissue by serological screening of a breast cancer library. Cancer Res 2001 Mar. 1; 61(5):2055-61; Sahin, U., et al. Human neoplasms elicit multiple specific immune responses in the autologous host. Proc. Natl. Acad. Sci. USA 1995; 92: 11810-13; Scanlan, M. J., et al. Characterization of human colon cancer antigens recognized by autologous antibodies. Int. J. Cancer 1998; 76: 652-8; Scanlan, M. J., et al. Antigens recognized by autologous antibody in patients with renal-cell carcinoma. Int. J. Cancer 1999; 83: 456-64; Scanlan M J, et al. Humoral immunity to human breast cancer: antigen definition and quantitative analysis of mRNA expression. Cancer Immunity 1:4 [epub]), and is catalogued in three databases: the peptide database of T-cell defined tumor antigens (authored by members of the Ludwig Institute for Cancer Research (LICR) that is available on the website of Cancer Immunity, Journal of the Academy of Cancer Immunology, cancerimmunity.org/peptidedatabase/Tcellepitopes); the SYFPEITHI database of MHC ligands and peptide motifs (available on the website of Biomedical Informatics-Heidelberg, bmi-heidelberg.com/syfpeithi/) and the cancer immunome database available on the website of the LICR (licr.org/CancerImmunomeDB, formerly licr.org/SEREX.html).
SEREX is a method of immunoscreening tumor-derived cDNA expression libraries with cancer patient sera in order to identify molecules recognized by high titered IgG antibodies (Sahin, U., et al. Human neoplasms elicit multiple specific immune responses in the autologous host. Proc. Natl. Acad. Sci. USA 1995; 92: 11810-13) Approximately 1000 distinct antigens have been defined by SEREX analysis, including a number of etiologically and therapeutically significant cancer antigens, such as mutational antigens (e.g. p53, LKB1, BUB1; Scanlan, M. J., et al. Characterization of human colon cancer antigens recognized by autologous antibodies. Int. J. Cancer 1998; 76: 652-8; Scanlan, M. J., et al. Antigens recognized by autologous antibody in patients with renal-cell carcinoma. Int. J. Cancer 1999; 83: 456-64; Scanlan M J, et al. Humoral immunity to human breast cancer: antigen definition and quantitative analysis of mRNA expression. Cancer Immunity 1:4 [epub]), differentiation antigens (e.g. tyrosinase, NY-BR-1, rab 38; Jager D, et al. Identification of a tissue-specific putative transcription factor in breast tissue by serological screening of a breast cancer library. Cancer Res 2001 Mar. 1; 61(5):2055-61; Sahin, U., et al. Human neoplasms elicit multiple specific immune responses in the autologous host. Proc. Natl. Acad. Sci. USA 1995; 92: 11810-13; Jager D, et al. Serological cloning of a melanocyte rab guanosine 5′-triphosphate-binding protein and a chromosome condensation protein from a melanoma complementary DNA library. Cancer Res 2000 Jul. 1; 60(13):3584-91), overexpressed gene products (e.g. Her2neu, TPD52, eIF4-gamma; Scanlan M J, et al. Humoral immunity to human breast cancer: antigen definition and quantitative analysis of mRNA expression. Cancer Immunity 1:4 [epub]; Chen, Y.-T., et al. Identification of human tumor antigens by serological expression cloning. In: S. A. Rosenberg (ed.). Principles and Practice of Biologic Therapy of Cancer, pp. 557-570. Philadelphia: Lippincott Williams & Wilkins, 2000) and cancer/testis (CT) antigens (e.g. MAGE-1, NY-ESO-1, SSX-2; Chen, Y.-T., et al. A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening. Proc. Natl. Acad. Sci. USA. 1997; 94: 1914-18; Sahin, U., et al. Human neoplasms elicit multiple specific immune responses in the autologous host. Proc. Natl. Acad. Sci. USA 1995; 92: 11810-13).
CT antigens represent a group of shared, tumor-specific antigens expressed exclusively in developing germ cells of the testis and fetal ovary, as well as in placental trophoblast, and most notably, in a proportion of human cancers of diverse origins (Chen, Y.-T., et al. Identification of human tumor antigens by serological expression cloning. In: S. A. Rosenberg (ed.). Principles and Practice of Biologic Therapy of Cancer, pp. 557-570. Philadelphia: Lippincott Williams & Wilkins, 2000). These antigens elicit spontaneous cellular (Van den Eynde, B. J. and van der Bruggen, P. (1997) Curr. Opin. Immunol. 9,684-693) and humoral immune responses (Stockert, E., et al. (1998) J. Exp. Med. 187, 1349-1354) in some cancer patients. On the basis of tissue-restricted expression and immunogenicity, CT antigens are attractive targets for vaccine-based immunotherapies. In general, CT antigens are expressed in 20-40% of specimens from a given tumor type (Sahin U, et al. 1998. Expression of multiple cancer/testis antigens in breast cancer and melanoma: basis for polyvalent CT vaccine strategies. Int J Cancer 78:387-89; Scanlan M J et al. 2000. Expression of cancer-testis antigens in lung cancer: definition of bromodomain testis-specific gene (BRDT) as a new CT gene, CT9. Cancer Lett. 150:155-64; Van den Eynde B J and van der Bruggen P. 1997. T cell defined tumor antigens. Curr Opin Immunol 9:684-693). One exception to this is synovial sarcoma, in which 80% of specimens express NY-ESO-1 (Jungbluth A A, et al. 2001. Monophasic and biphasic synovial sarcomas abundantly express cancer/testis antigen NY-ESO-1 but not MAGE-A1 or CT7. Int J Cancer 94:252-6) and MAGE antigens (Antonescu C R, et al. MAGE antigen expression in monophasic and biphasic synovial sarcoma. Hum Pathol 2002 February; 33(2):225-9); the expression of which are often homogeneous throughout the tumor. Thus, identification of additional CT antigens and other genes having a tumor-associated expression profile is needed for the development of additional therapeutics and diagnostics to permit effective treatment and diagnosis of a broader group of cancer patients.